基于“AS1411-脂质体-SH2超亲体”复合体靶向治疗非小细胞肺癌的新策略
结题报告
批准号:
81974468
项目类别:
面上项目
资助金额:
55.0 万元
负责人:
曹轩
依托单位:
学科分类:
肿瘤靶向治疗
结题年份:
2023
批准年份:
2019
项目状态:
已结题
项目参与者:
曹轩
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中文摘要
酪氨酸激酶异常活化在癌症的发生和发展中起决定性作用,抑制酪氨酸激酶活性的药物在癌症靶向治疗药物中占大多数,这些药物靶点单一,由于基因突变容易产生耐药性。SH2超亲体(SH2结构域超级亲和突变体)不仅具有跟磷酸化的酪氨酸(pY)结合的特异性与高亲和力,而且大大减弱了对pY前后序列的偏好性,能结合更多种类的pY多肽。“核酸适体-脂质体-SH2超亲体”复合体可以通过核酸适体AS1411特异性识别并结合癌细胞,将脂质体包裹的SH2超亲体蛋白完整地导入细胞内,在癌细胞内SH2超亲体可以跟众多含pY蛋白强烈结合,广谱地阻断相关的信号通路,抑制癌细胞的增殖与迁移、诱导癌细胞的凋亡,达到高效治疗癌症的效果,既能保证特异性,又能实现多靶点性,有效地避免耐药性和毒副作用。本项研究以非小细胞肺癌作为示范,也可以扩展到其它类型的癌症。因此,“AS1411-脂质体-SH2超亲体”有望成为靶向抗癌新策略。
英文摘要
Aberrant activation of tyrosine kinases plays a pivotal role in the carcinogenesis and development of cancer. A number of cancer-targeted drugs have been evaluated and approved for clinical use. Most of them are developed against tyrosine kinases. However, the accompanying drug resistance is inevitable for these single-target drugs owing to gene mutations. SH2 superbinder, a triple-mutant of the Src Homology 2 (SH2) domain, may specifically recognize and bind to the phosphotyrosine (pY) residues with higher affinity and less preference in different pY proximal sequence contexts than the natural SH2 domains, thus SH2 superbinder might capture diverse pY peptides when applied in large quantities. The complex of "Aptamer-liposome- SH2 superbinder" may specifically recognize and bind the target molecules on the cell surface of cancer cells via aptamer AS1411 and effectively translocate intact SH2 superbinder protein into cancer cells by liposome. SH2 superbinder protein can strongly bind with numerous pY-containing proteins and block multitude pY-based signaling pathways as the broad-spectrum inhibitor, which shows potent anti-cancer efficacy by inhibiting proliferation, metastasis and inducing apoptosis. With the advantages of accurate delivery and multitude-target blockade, the complex of "AS1411-liposome-SH2 superbinder" may overcome the defects of side-effect and drug resistance of the conventional cancer-targeted drugs. This study makes non-small cell lung cancer (NSCLC) as a model. The complex may also aim at other kinds of cancers. Thus, "AS1411-liposome-SH2 superbinder" complex has the potential to act as a promising novel strategy for the targeted therapy of cancers.
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DOI:10.7150/thno.72269
发表时间:2022
期刊:THERANOSTICS
影响因子:12.4
作者:Wang, Meng;Liu, An Dong;Niu, Qian;Feng, Xiao;Zheng, Yuan-Yi;Chen, Shuai-Jun;Xu, Hui;Li, Qian;Hou, Guo-Qing;Bi, Xiao-Yang;Lu, Yu-Zhi;Cheng, Pei-Pei;Liang, Li-Mei;Jiang, Ye-Han;Zhao, Li-Qin;Liu, Fei;Song, Lin-Jie;Zhou, Li-Ling;Xiao, Ling-Yan;Chen, Feng;Li, Shawn Shun-Cheng;Ma, Wan-Li;Cao, Xuan;Ye, Hong
通讯作者:Ye, Hong
DOI:10.1186/s13046-023-02686-1
发表时间:2023-05-10
期刊:Journal of experimental & clinical cancer research : CR
影响因子:--
作者:
通讯作者:
DOI:10.1002/ctm2.337
发表时间:2021-03
期刊:Clinical and translational medicine
影响因子:10.6
作者:Liu AD;Zhou J;Bi XY;Hou GQ;Li SS;Chen Q;Xu H;Cao X
通讯作者:Cao X
DOI:10.1038/s41419-023-06344-4
发表时间:2023-12-09
期刊:CELL DEATH & DISEASE
影响因子:9
作者:Xu, Hui;Tan, Ming;Hou, Guo-Qing;Sang, Ya-Zhou;Lin, Li;Gan, Xiao-Cai;Cao, Xuan;Liu, An-Dong
通讯作者:Liu, An-Dong
调控细胞迁移的新信号通路网络及其在乳腺癌转移中的作用
  • 批准号:
    31771541
  • 项目类别:
    面上项目
  • 资助金额:
    60.0万元
  • 批准年份:
    2017
  • 负责人:
    曹轩
  • 依托单位:
PTEN和p110调节p85的GAP功能、Rac1活性和成纤维细胞运动与转化的分子机制研究
  • 批准号:
    31571431
  • 项目类别:
    面上项目
  • 资助金额:
    65.0万元
  • 批准年份:
    2015
  • 负责人:
    曹轩
  • 依托单位:
国内基金
海外基金